Angiogenesis, the growth of new blood vessels, is a complex process involving the disruption of vascular basement membranes, the migration and proliferation of endothelial cells, and the subsequent formation and maturation of blood vessels. In cases in which there is excessive or insufficient angiogenesis, various pathological disorders arise including, for example, ischemic myocardial conditions, psoriasis, and peripheral vascular conditions.
Several mediators are known to positively or negatively regulate the angiogenic process. The administration of such mediators has therefore been suggested as a therapeutic strategy to either promote or reduce vascularization for the treatment of angiogenic disorders. Given that its cognate receptor is expressed almost exclusively on vascular endothelial cells, vascular endothelial growth factor (VEGF) is one of the most promising angiogenic ligands targeted for therapeutic purposes. In this regard, VEGF receptors are typically upregulated under ischemic conditions and consequently, the administration of recombinant VEGF augments the development of collateral vessels and improves the function of peripheral and myocardial ischemic tissues.
Another polypeptide factor which directly influences the migratory and proliferative activity of human endothelial cells and which is recognized as a mediator of human angiogenesis is fibroblast growth factor (FGF). FGF is a potent human endothelial cell mitogen which increases the survival and proliferation of human endothelial cells. FGF activity also results in an increase in skeletal and smooth muscle growth, neurogenesis, and organ/tissue repair.
Cyclooxygenase 2 (COX-2) is another factor that is involved in normal angiogenesis, as well as tumor-associated angiogenesis, tumor growth, and tumor metastasis. COX-2 is involved in the formation of prostanoids from arachidonic acid and is induced in response to a wide range of cellular signals in normal tissues.
Increasing angiogenesis when desirable and decreasing angiogenesis when undesirable, e.g., by modulating the activity of angiogenic factors, such as VEGF, continues to pose a significant challenge. The half-life of VEGF protein, e.g., is extremely short and the administration of high doses of VEGF is often associated with hypotension. Furthermore, the systemic administration of VEGF can cause the promiscuous induction of angiogenesis in healthy host tissues and as a result, cause blindness, increase the aggressiveness of tumor cells, and lead to a multitude of other negative side-effects. On the other hand, if VEGF is delivered in insufficient amounts, angiogenesis is not induced and thus, no significant therapeutic benefit is achieved.
Thus, there exists a need for an effective method of both inducing and inhibiting angiogenesis in a target tissue.